PROJECT SUMMARY PROJECT 3 ? ADOLESCENT NICOTINE Nicotine is one of the most commonly used drugs among adolescents. Several studies link tobacco and nicotine use in human adolescence and subsequent problems in adulthood, including later tobacco, alcohol, cocaine and other illicit drug use. Individuals who smoke cigarettes before the age of 15 are estimated to be eighty times more likely to use illegal drugs such as cocaine than those who do not. In addition, studies in animals have shown that adolescent nicotine exposure affects nicotine and cocaine reward and sensitivity in rodents; we have shown that repeated exposure to low doses of nicotine in adolescence clearly induces age- specific enhancement of the rewarding effects of nicotine and other drugs of abuse that persisted long after the termination of nicotine exposure. However, the molecular and genetic mechanisms underlining nicotine- induced enhancements to the reward effects are still unclear. This project will identify risk associated genes and gene networks using highly diverse mouse genetic populations. We will use inbred Collaborative Cross (CC)/ Diversity Outcross (DO) founder and CC strains to measure nicotine reward using the conditioned place preference (CPP) test after exposure to nicotine in early adolescence. These data will be used to conduct genetic correlations across behaviors including impulsivity, cocaine self-administration (IVSA), acute and sensitized cocaine induced locomotor activation and circadian rhythms to determine common genetic architecture shared among traits. We will also study changes in striatal dopamine (DA) signaling in CC strains that exhibit extreme behavioral responses to nicotine. Secondly, we will correlate nicotine CPP behaviors with gene expression changes in the striatum of CC mice to further identify potential candidate genes, gene networks and biological mechanisms that may mediate the effects of adolescent nicotine exposure. Finally, we will map nicotine reward in the CPP test in a large DO cohort after exposure to nicotine during early adolescence. Genotype data will be used to reveal QTLs specific to nicotine in adolescence as well as identify common QTLs shared between impulsivity, cocaine self-administration, cocaine sensitization and circadian rhythms phenotypes generated by the various projects and cores within the Center for Systems Neurogenetics of Addiction. Genetic mapping data along with expression studies will be used to identify candidate genes for validation studies in novel mouse models made through genome editing technologies. If successful, this application promises to have a significant positive impact on human health through the identification of genetically high-risk individuals who would benefit from proactive interventions following nicotine exposure in adolescence.